Engineered MOF-Enzyme Nanocomposites for Tumor Microenvironment-Activated Photodynamic Therapy with Self-Luminescence and Oxygen Self-Supply.

Photodynamic therapy (PDT) is a promising strategy for cancer treatment. However, its efficiency is hindered by three key parameters, namely, limited penetration depth of external light, tumor hypoxia, and self-aggregation of photosensitizers. Herein, we fabricated a novel "all-in-one" chemiluminescence-PDT nanosystem through the integration of an oxygen-supplying protein (hemoglobin, Hb) and a luminescent donor (luminol, Lum) in hierarchically engineered mesoporous porphyrinic metal-organic framework (MOF) nanoparticles. Mechanistically, the in situ chemiluminescence of Lum is activated by the high concentration of H2O2 in 4T1 cancer cells and further catalyzed by Hb and then absorbed by the porphyrin ligands in MOF nanoparticles through chemiluminescence resonance energy transfer. The excited porphyrins then sensitize oxygen supplied by Hb to produce sufficient reactive oxygen species that kill cancer cells. The MOF-based nanocomposite demonstrates excellent anticancer activity both in vitro and in vivo, with eventually a 68.1% tumor inhibition rate after intravenous injections without external light irradiation. This self-illuminating, oxygen-self-supplying nanosystem integrates all essential components of PDT into one simple nanoplatform, demonstrating great potential for the selective phototherapy of deep-seated cancer.

Self-Assembled Corrole/Chitosan Photothermal Nanoparticles for Accelerating Infected Diabetic Wound Healing.

Microvascular dysfunction caused by hyperglycemia leads to slow healing of diabetic wounds and significantly increases the risk of bacterial infection. The misuse of antibiotics can also lead to bacterial resistance, making the management of diabetic wounds more challenging. Thus, developing new antibacterial agents or strategies to overcome antibiotic resistance is highly pursued. Herein, novel supramolecular photothermal nanoparticles (MCC/CS NPs), assembled from mono-carboxyl corrole (MCC) and chitosan via hydrogen bonding and π-π stacking, are developed and used for treating bacterial wound infection. The MCC molecules possess good photothermal performance and the chitosan with inherent bioactivity can exert moderate antibacterial effects. The aggregation of MCC in MCC/CS NPs induced by chitosan-templated self-assembly further quenches molecular fluorescence and realizes an extraordinary photothermal conversion efficiency of 66.4%. Moreover, the highly positively charged MCC/CS NPs can selectively target bacteria via electrostatic interactions. Under near-infrared laser irradiation, the MCC/CS NPs achieve potent photothermal and inherent antimicrobial synergistic effects against Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA) in vitro. Furthermore, the bacteria-infected diabetic wound model confirms that the MCC/CS NPs can effectively kill drug-resistant bacteria, accelerate wound healing and angiogenesis, and show good biocompatibility, representing a novel and efficient photothermal antibacterial nanoplatform.

Efficient oral insulin delivery enabled by transferrin-coated acid-resistant metal-organic framework nanoparticles.

Oral protein delivery is considered a cutting-edge technology to improve patients' quality of life, offering superior patient compliance and convenience compared with injections. However, oral protein formulation has stagnated because of the instability and inefficient penetration of protein in the gastrointestinal tract. Here, we used acid-resistant metal-organic framework nanoparticles (UiO-68-NH2) to encapsulate sufficient insulin and decorated the exterior with targeting proteins (transferrin) to realize highly efficient oral insulin delivery. The UiO-68-NH2 nanocarrier with proper pore size achieved high insulin loading while protecting insulin from acid and enzymatic degradation. Through receptor-mediated transcellular pathway, the transferrin-coated nanoparticles realized efficient transport across the intestinal epithelium and controlled insulin release under physiological conditions, leading to a notable hypoglycemic effect and a high oral bioavailability of 29.6%. Our work demonstrates that functional metal-organic framework nanoparticles can protect proteins from the gastric environment and overcome the intestinal barrier, thus providing the possibility for oral biomacromolecule delivery.

Stimuli-responsive charge-reversal MOF@polymer hybrid nanocomposites for enhanced co-delivery of chemotherapeutics towards combination therapy of multidrug-resistant cancer.

Combination chemotherapy is a promising strategy for cancer treatment in clinics especially when multidrug-resistant cancer is emerging. One significant challenge remains in achieving sufficient multi-drug delivery into tumor cells to maximize the synergetic therapeutic effect, as it is hard to concentrate drugs in drug-resistant cancer. Therefore herein, metal-organic framework (MOF)-based polymer-coated hybrid nanoparticles (NPs) were devised and constructed for the co-delivery of doxorubicin and cisplatin to enhance combination therapy of multidrug-resistant cancer. The MOF@polymer nanocarrier combined the merits of high multi-drug loading capacity, physiological stability, and tumor microenvironment pH-responsiveness, facilitating simultaneous delivery of drugs into cancer cells and making the most of synergistic antitumor effect. Remarkably, this hybrid nanocarrier maintains a negative surface charge during circulation to guarantee a stable and prolonged process in vivo, and then exposes inner positive MOF after degradation of the outer polymer in the acidic tumor microenvironment to promote multi-drug release, cellular internalization, nuclear localization, and tumor penetration. In vitro and in vivo studies with drug-resistant MCF-7/ADR cancer suggested that the nanocarrier could achieve increased accumulation of drugs in solid tumors, remarkable tumor elimination results as well as minimized side effects, indicating an improved efficacy and safety of combination chemotherapy. MOF@polymer hybrid nanocarriers provide new insights into the development of stimuli-responsive co-delivery systems of multiple drugs.

Defect-engineered porphyrinic metal-organic framework nanoparticles for targeted multimodal cancer phototheranostics.

Defect-engineered porphyrinic MOF nanoparticles were fabricated with an in situ one-pot protocol using cypate as the co-ligand and modulator. This multifunctional nanoplatform integrated the photothermal and multimodal imaging properties of cypate with the photodynamic effects of porphyrins, thus achieving targeted multimodal cancer phototheranostics after folic acid modification.

One-Pot Fabrication of Hollow Porphyrinic MOF Nanoparticles with Ultrahigh Drug Loading toward Controlled Delivery and Synergistic Cancer Therapy.

Hollow nanostructures have attracted significant research interest in drug delivery systems due to their high capacities for drug loading and unique physicochemical properties, showing great potential in specific biomedical applications. Herein, hollow porphyrinic metal-organic framework (H-PMOF) nanoparticles with a mesoporous spherical shell have been fabricated via a facile self-sacrificial ZIF-8 nanoparticle template strategy. The H-PMOF nanoplatform not only demonstrates a greatly enhanced photodynamic therapy efficacy compared with nonhollow porphyrinic MOF nanoparticles but also can be used as a superior drug carrier to co-load doxorubicin (DOX) and indocyanine green (ICG) with an ultrahigh drug-loading capacity of 635%. Furthermore, cancer cell membrane camouflage of the (DOX and ICG)@H-PMOF composite nanoparticles affords a biomimetic nanoplatform, that is, (DOX and ICG)@H-PMOF@mem (DIHPm for short), with an outstanding homologous tumor-targeting and immune-escaping ability. Interestingly, DIHPm shows both pH-controlled and near-infrared laser-triggered DOX release. Both in vitro and in vivo studies of DIHPm demonstrate an excellent imaging-guided synergistic photodynamic/photothermal/chemotherapy anticancer activity with negligible systemic toxicity. The development of the high-performance H-PMOF nanoplatform provides new insights into the design of MOF-based multifunctional nanomedicines for combination cancer therapy and precise theranostics.

Carboxymethyl chitosan-based nanogels via acid-labile ortho ester linkages mediated enhanced drug delivery.

This work described the preparation of two type nanogels based on the crosslinking between carboxymethyl chitosan (CMCS) and two different crosslink agents, an acid-labile cyclic ortho ester compound with dual epoxy end groups (OEDe) or corresponding non-sensitive ethyleneglycol diglycidyl ether (EGDE). The particle size, zeta potential, and micromorphology were characterized by dynamic light scattering and electron microscopy, respectively. Nanogels' stability was also investigated at physiological environments. Doxorubicin hydrochloride as a therapeutic drug model was efficiently embedded into nanogels. The pH-triggered size changing, degradation and drug release were then investigated at three different pH values. Cellular uptake and cytotoxicity evaluation demonstrated that NG1/DOX could be successfully degraded and efficiently release DOX in acid cell organelles, leading to higher cytotoxicity than NG2/DOX. The accumulation and penetration of these DOX-loaded nanogel were then investigated by tumor-like multicellular spheroids (MCTS). The results indicated that the acid-degradable nanogels can deliver more DOX into the inner of MCTS by the hydrolysis of ortho ester bonds, thus efficiently inhibit the growth of MCTS. All results suggested that the acid-degradable nanogels could be degraded in mildly acidic conditions and remain stable at physiological environment, which indicated that the acid-degradable nanogels would be potentially useful as drug carriers.

pH-sensitive carboxymethyl chitosan hydrogels via acid-labile ortho ester linkage for potential biomedical applications.

Hydrogel systems with favorable biocompatibility and biodegradability are of much interest for application in biomaterials and tissue engineering. In this study, a new ortho ester-based acid-labile crosslink agent with dual-epoxy end groups was synthesized and crosslinked with carboxymethyl chitosan (CMCS) at different molar ratios to prepare a series of pH-sensitive hydrogels for drug delivering. Doxorubicin (DOX) was then readily loaded into the hydrogels and the in vitro release profiles indicated that the release rate increased rapidly while pH decreased from 7.4 to 5.0, which is consistent with the degradation rate of these hydrogels at corresponding pH conditions. In addition, results from MTT assay and flow cytometry demonstrated that these CMCS-based hydrogels and their degradation products have no cytotoxicity against SH-SY5Y and 293T cells. Therefore, the prepared acid-labile hydrogels could be applied in tumorous drug delivery systems and peritumoral implantation therapy by further optimization.

Well-Defined Poly(Ortho Ester Amides) for Potential Drug Carriers: Probing the Effect of Extra- and Intracellular Drug Release on Chemotherapeutic Efficacy.

To compare the chemotherapeutic efficacy determined by extra- and intracellular drug release strategies, poly(ortho ester amide)-based drug carriers (POEAd-C) with well-defined main-chain lengths, are successfully constructed by a facile method. POEAd-C3-doxorubicin (DOX) can be rapidly dissolved to release drug at tumoral extracellular pH (6.5-7.2), while POEAd-C6-DOX can rapidly release drug following gradual swelling at intracellular pH (5.0-6.0). In vitro cytotoxicity shows that POEAd-C3-DOX exhibits more toxic effect on tumor cells than POEAd-C6-DOX at extracellular pH, but POEAd-C6-DOX has stronger tumor penetration and inhibition in vitro and in vivo tumor models. So, POEAd-C6-DOX with the intracellular drug release strategy has stronger overall chemotherapeutic efficacy than POEAd-C3-DOX with extracellular drug release strategy. It is envisioned that these poly(ortho ester amides) can have great potential as drug carriers for efficient chemotherapy with further optimization.

Stepwise targeted drug delivery to liver cancer cells for enhanced therapeutic efficacy by galactose-grafted, ultra-pH-sensitive micelles.

To promote drug accumulation and cell-killing ability at tumor tissue, we have prepared a stepwise targeted drug delivery system that can remain stealthy and long-circulating in the blood vessels, improve drug retention at extracellular stimuli, enhance cellular uptake through special targeting ligands, and then achieve rapid drug release to improve toxicity to tumor cells at intracellular stimuli. Herein, galactose-grafted, ultra-pH-sensitive drug carriers (POEAd-g-LA-DOX micelles), which could respond to both extracellular and intracellular pH, and combine with galactose-receptors in cell membrane, were constructed by a facile method, therefore achieving: (i) remaining stable at pH 7.4; (ii) responding to tumoral extracellular pH following gradually larger nanoparticles (NPs); (iii) conjugating receptors in the cell membrane of liver cancer through surface galactose-ligands of micelles; (iv) being sensitive to tumoral intracellular pH following further swelling for rapid drug release. In vitro cytotoxicity and cellular uptake measurement showed that POEAd-g-LA20-DOX micelle was more easily internalized and more toxic effect on tumor cells than free DOX. Moreover, in vivo biodistribution and tumor inhibition examinations demonstrated that POEAd-g-LA20-DOX formulation had more superior efficacy to significantly enhance drug accumulation in tumor, and then restrain tumor growth while decreasing drug concentration in heart. STATEMENT OF SIGNIFICANCE: Chemotherapeutic efficacy is limited by poor tumor selectivity, which also causes severe toxicity in normal tissues and organs, although many targeted drug delivery systems have been developed by passive targeting strategies or active targeting strategies with specific targeting ligands in recent years. Herein, galactose-grafted, ultra-pH-sensitive, ortho ester-based drug carriers, which can respond to both extracellular and intracellular pH, and target to galactose-receptors in cell membrane, have been successfully constructed by facile method, therefore achieving stepwise targeting to microenvironment of liver cancer and then enhancing drug accumulation and tumor inhibition. The strategy of designing dual-stimuli-responsive copolymers can be potentially useful, and extrapolated to synthesizing other categories of highly labile drug carriers in a range of biomedical applications.